In 2006, 173 million composite and amalgam restorations were placed in the U.S. and clinical data suggest that >100 million were replacements. Since composites fail at a rate double that of amalgam, the emphasis on replacement therapy will increase with the elimination of amalgam. Recurrent decay is the primary reason for failure and 80-90% of recurrent decay is located at the gingival margin of the composite restoration. At this margin, the adhesive and its bond with dentin is the barrier between the restored tooth and the oral environment. In vivo degradation of the adhesive bond follows a cascade of events; these events are provoked by matrix metalloproteinases (MMPs) that degrade water-rich collagen that is not shielded by mineral or resin; acids and esterases released by the residual bacteria that contaminate the cavity; esterases and oral fluids that degrade the adhesive. Establishing and maintaining the interfacial integrity of the adhesive/dentin (a/d) bond has been a critical roadblock to durable composite restorations. Our approach involves a threefold strategy that: (i) exploits peptide engineering to disinfect the cavity and remineralize deficient dentin - the peptides are localized at the substrate by anchoring to the adhesive and dentin; (ii) engineers resins to resist chemical and enzymatic hydrolysis; and (iii) employs iterative feedback between synthesis, characterization and modeling to predict properties and promote targeted optimization of the adhesive. Combining bio- enabled techniques with synthesis of novel polymers, the overall hypothesis is that an adhesive formulation that achieves a durable, integrated a/d interfacial bond will provide an enhanced barrier to cariogenesis as compared to state-of-the-art dentin adhesives. Our goal is to show how altering the material chemistry and anchoring targeted peptides will lead to predictable changes in properties (resist chemical and enzymatic hydrolysis, disinfect the cavity, remineralize the dentin) and to optimize features for in situ a/d bond formation and interfacial integrity based on kinetics, fatigue, multi-scale structure/property characterization and predictiv modeling. The specific Aims are: 1) to synthesize the most promising formulation that provides disinfection and remineralization using peptide engineering and iterative experimental/computational approaches; 2) to determine the hydrolytic and enzymatic resistance of the versatile resin matrices; 3) to test the bio-physicochemical and mechanical properties of the new adhesive at the interface between composite and caries-free and caries-affected dentin.